For the previous 15 years of support on this program project grant, we have sought to identify psychosocial factors that increase cardiovascular disease risk and to understand the biobehavioral mechanisms whereby increased risk is mediated. During the current 5-year period of support, we have met our broad objectives to: 1) document the clustering of psychosocial and biobehavioral risk factors for CVD in persons of low socioeconomic status; 2) document the important influence of early environments on this clustering; and 3) document the role of brain serotonergic function as an important contributor to this clustering. We have also initiated a major new research initiative - identification of polymorphisms of serotonin-related genes as a new means of documenting the importance of serotonergic mechanisms in clustering of psychosocial and biobehavioral factors that increase CVD risk. Based on findings of extensive associations between polymorphisms of the serotonin transporter and monoamine oxidase A genes and phenotypes in every system we have studied during the current PPG, we propose now to undertake a large scale and ambitious study, involving up to 500 hostile probands and over 500 of their siblings, to identify genetic variants - using family-based association studies of candidate genes and loci - that influence the expression of hostility and the other psychosocial and biobehavioral enophenotypes that cluster with hostility in the same individuals and low SES groups. Project 1 will search for genetic variants that influence hostility, personality, and cardiovascular, neuroendocrine, and platelet functions, as well as circulating inflammatory markers at rest and in response to stress. Project 2 will search for genes that influence glucose metabolism and the metabolic syndrome. Project 3 will search for genes that influence ambulatory markers of stress in the real world. Five Cores will support the Projects. Representing a new collaboration between investigators in the Duke Behavioral Medicine Research Center and the Center for Human Genetics, the proposed research could identify genetic variants that interact with stressful environments to increase CVD risk via effects on healthdamaging psychosocial and biobehavioral endophenotypes - thereby increasing understanding of pathogenic mechanisms and raising the possibility of being able to identify highly susceptible persons who may be candidates for both secondary and primary prevention trials.